Alkohol, Berufsunf?lle und ihre Folgen

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Insulin dependence of M2 pyruvate kinase in primary culture of human liver

In the basal state, the presence of L pyruvate kinase (LPK) was constantly observed in primary human liver cell cultures initiated from explants, when cells were examined by immunofluorescence and double labelling. After short-term insulin incubation, M pyruvate kinase (MPK) appeared. Therefore, both LPK and MPK were located in the same cells. We previously obtained the same results in isolated rat hepatocytes in which we demonstrated that short-term regulation of M2PK by insulin was a function of dose and/or incubation time. The present work established that similar conditions govern the regulation of this isozyme in vitro in human hepatocytes.     

Short duration, high dose, alternating chemotherapy in metastatic neuroblastoma. (ENSG 3C induction regimen). The European Neuroblastoma Study Group

Fifty-one children, aged from 15 months to 13 years 5 months with metastatic neuroblastoma presenting sequentially at the participating institutions received four 3 to 4 weekly courses of high dose multiagent chemotherapy. High dose cisplatin (200 mg m-2) combined with etoposide (500 mg m-2), HIPE, was alternated with ifosfamide (9 g m-2), vincristine (1.5 mg m-2), and adriamycin (60 mg m-1), IVAd. Disease status was re-evaluated 3 to 4 weeks after the fourth course and the response classified according to the International Neuroblastoma Response Criteria (INRC). The overall response rate in evaluable patients was 55% and response rates by site were: bone marrow 67% (complete response 47%); bone scan 68%; primary tumour 61%, and urinary catecholamine metabolites (VMA/HVA) 95%. Serial 51Cr EDTA renal clearance studies showed a glomerular filtration rate (GFR) decline in 40% of patients but in only seven cases to below 50% of the pretreatment value. There was no instance of renal failure during induction, though two patients developed severe renal failure following 'megatherapy' given to consolidate remission. Serial audiometry showed a significant decline in hearing at frequencies above 2,000 Hz in 37% of children but at or below 2,000 Hz in only 17%. Neutropenia and thrombocytopenia were severe and intravenous antibiotics were required after 30% of courses. Each of two treatment-related deaths occurred during pancytopenia following courses of IVAd. Complete, or greater than 90%, removal of primary site tumour was possible in 70% of cases following this induction regimen and 75% of patients proceeded to elective megatherapy within a median time of 24 weeks after diagnosis. This short intensive induction programme is highly effective at achieving cytoreduction, enabling early surgery and early megatherapy procedures. It is, however, too early to draw firm conclusions about the impact of this approach to treatment on the cure rate.     

Intravenous single-dose ceftriaxone treatment of chancroid.

The antimicrobial susceptibility of Haemophilus ducreyi varies according to the geographic region. Increased resistance to trimethoprim and/or sulfamethoxazole led the Centers for Disease Control to recommend 250 mg ceftriaxone as a single intramuscular dose for chancroid. Intravenous or muscular routes of administration result in equivalent bioavailability. To avoid side effects such as syringe abscess and lidocaine intolerance, we prefer intravenous ceftriaxone therapy. The efficacy of this regimen is reported in 3 cases of chancroid. The intravenous administration of 1 g of ceftriaxone in chancroid seems to be as effective as administration by the intramuscular route, but it may lower the risk of syringe abscess, lidocaine intolerance and the emergence of resistant strains.     

Influence of alkyl-chain fluorination on the action of mammary tumor inhibiting 2,3-bis(hydroxyphenyl)butanes and 2,3-bis(hydroxyphenyl)but-2-enes

trans-1,2-Bis(trifluoromethyl)-1,2-bis(4- and 3-hydroxyphenyl)ethenes 2 and 4 were prepared by reductive coupling (TiCl4/Zn/pyridine) of the methoxy-substituted alpha, alpha, alpha-trifluoroacetophenones, separation of the resulting cis- and trans-stilbene derivatives, and ether cleavage with BBr3. The cis-stilbenes were catalytically hydrogenated to give meso-1,1,1,4,4,4-hexafluoro-2,3-bis(4- and 3-hydroxyphenyl)butanes 6 and 8. Compounds 2, 4, 6, and 8 showed 2- to 10-fold increased binding affinities for the estradiol receptor (E2R) and enhanced estrogenicity in the uterine weight test of the immature mouse compared to their unfluorinated analogues. Compound 8 exhibited a 46% inhibition of the estrone-stimulated uterine growth. Antitumor activity was evaluated with use of the transplantable, hormone-dependent MXT mammary tumor of the BD2F1 mouse. All compounds showed tumor growth inhibitory activity corresponding to their RBA values. The most interesting compound 8 led to a significant inhibition of the tumor growth on the DMBA-induced hormone-dependent mammary carcinoma of the Sprague-Dawley rat.     

New forms of work in general practice

A trial with job rotation between repetitive jobs failed within a year after initial enthusiasm among the workers. Stress may increase to an intolerable level with the number of tasks, with higher qualified work and due to the lack of familiarity with fellow workers in ever changing settings.     

Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man

Objective: Pantoprazole is a selective proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzymes in man. Due to the clinical importance of an interaction with anticoagulants, this study was carried out to investigate the possible influence of pantoprazole on the pharmacodynamics and pharmacokinetics of phenprocoumon. Methods: Sixteen healthy male subjects were given individually adjusted doses of phenprocoumon to reduce prothrombin time ratio (Quick method) to about 30–40% of normal within the first 5–9 days and to maintain this level. The individual maintenance doses remained unaltered from day 9 on and were administered until day 15. Additionally, on study days 11–15, pantoprazole 40 mg was given per once daily. As a pharmacodynamic parameter, the prothrombin time ratio was determined on days 9 and 10 (reference value) and on days 14 and 15 (test value), and the ratio test/reference was evaluated according to equivalence criteria. Results: The equivalence ratio (test/reference) for prothrombin time ratio was 1.02 (90% confidence interval 0.95–1.09), thus fulfilling predetermined bioequivalence criteria (0.70–1.43). The pharmacokinetic characteristics AUC_0–24h and C_max of S(−)-and R(+)-phenprocoumon were also investigated using equivalence criteria. Equivalence ratios and confidence limits of AUC_0–24h and of C_max of S(−)-phenprocoumon (0.93, 0.87–1.00 for AUC_0–24h; 0.95, 0.88–1.03 for C_max) and of R(+)-phenprocoumon (0.89, 0.82–0.96; 0.9, 0.83–0.98) were within the accepted range of 0.8–1.25. Conclusion: Pantoprazole does not interact with the anticoagulant phenprocoumon on a pharmacodynamic or pharmacokinetic level. Concomitant treatment was well tolerated. Received: 26 January 1996/Accepted in revised form:22 May 1996     

'In situ' high pressure confocal Ca(2+)-fluorescence microscopy in skeletal muscle: a new method to study pressure limits in mammalian cells.

We combined 'in situ' high pressure microscopy with confocal laser scanning microscopy to directly study Ca2+ homeostasis in intact mammalian (murine) skeletal muscle fibres during high pressure exposure up to 35 MPa. Cytosolic Fluo-4 and mitochondrial Rhod-2 Ca2+ fluorescence were simultaneously monitored. To separate changes in Ca2+ and direct/indirect effects of pressure on the dye, experiments in permeabilized ('skinned') muscle fibres were performed at a fixed Ca2+ concentration. Normalized Fluo-4 fluorescence sharply declined up to 10 MPa but showed a plateau between 10 MPa and -35 MPa. In the intact fibre, Fluo-4 fluorescence exponentially decreased during pressurization to 35 MPa with a pressure constant of pi-5 MPa whereas mitochondrial Rhod-2 fluorescence exponentially increased with a four-fold larger pi. Holding the pressure at 35 MPa almost did not change Fluo-4 fluorescence. However, Rhod-2 fluorescence started to decrease after -40 min. Upon decompression, Rhod-2 and Fluo-4 fluorescence increased exponentially with similar pi. However, initial Fluo-4 fluorescence values were not restored. Our results are in agreement with pressure induced Ca2+ leakage from the sarcoplasmic reticulum. Ca2+ might then be taken up in large amounts by mitochondria preventing cytosolic increase in Ca2+. Prolonged pressure applications (-40 min at 35 MPa) seem to destabilize mitochondrial function with release of Ca2+ from mitochondria back into the cytosol and eventually mechanical activation resulting in irreversible contractures. The pressure induced disturbance of Ca2+ homeostasis might have important implications for the pressure exposure limits and/or dive profiles of deep sea mammals.